The present invention relates to certain novel hydroxy-ML-236B derivatives, as well as salts and esters of these compounds, and processes for preparing them and methods and compositions using them.
ML-236B, which can exist in the form of an acid (known as "ML-236B carboxylic acid") or a lactone (known as "ML-236B lactone"), was disclosed in United Kingdom Patent Specification No. 1,453,425 and, in its lactone form, has the formula (A): ##STR1##
Subsequently, United Kingdom Patent Specification No. 1,555,831 disclosed a variety of salts and esters of ML-236B. ML-236B and its salts and esters were found to inhibit the biosynthesis of cholesterol by competing with 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the rate-determining enzyme for cholesterol biosynthesis; these compounds were thus found to exhibit a very marked ability to reduce serum cholesterol levels.
Subsequently, certain 3-hydroxy-ML-236B derivatives were isolated as products of the animal metabolism of ML-236B lactone and similar derivatives were found to be produced by the enzymatic hydroxylation of ML-236B lactone or carboxylic acid or salts or esters thereof, effected by means of various microorganisms. These processes are disclosed in U.S. Pat. No. 4,346,227 and UK Patent No. 2,111,052, and the compounds thus produced are described in those patents as M-4, M-4', IsoM-4 and IsoM-4'. These compounds were found to have an ability to inhibit the biosynthesis of cholesterol which is at least comparable with and, in some instances, substantially exceeds that of ML-236B itself.
ML-236B and its derivatives, including the M-4 and M-4' compounds, are thus of therapeutic value for the treatment of hyperlipaemia and the prophylaxis of arteriosclerosis.
A structurally related group of compounds includes the mevinolin derivatives e.g. of U.S. Pat. No. 4,231,938, and a hydroxy derivative of such a compound is disclosed in U.S. Pat. No. 4,376,863; however, such compounds are structurally and conceptually different from those of the present invention and are prepared in a different way.
We have now discovered a series of novel hydroxy derivatives of ML-236B which likewise have a valuable ability to inhibit the biosynthesis of cholesterol.